Impact of cholesterol on voids in phospholipid membranes

Abstract

Free volume pockets or voids are important to many biological processes in cell membranes. Free volume fluctuations are a prerequisite for diffusion of lipids and other macromolecules in lipid bilayers. Permeation of small solutes across a membrane, as well as diffusion of solutes in the membrane interior are further examples of phenomena where voids and their properties play a central role. Cholesterol has been suggested to change the structure and function of membranes by altering their free volume properties. We study the effect of cholesterol on the properties of voids in dipalmitoylphosphatidylcholine (DPPC) bilayers by means of atomistic molecular dynamics simulations. We find that an increasing cholesterol concentration reduces the total amount of free volume in a bilayer. The effect of cholesterol on individual voids is most prominent in the region where the steroid ring structures of cholesterol molecules are located. Here a growing cholesterol content reduces the number of voids, completely removing voids of the size of a cholesterol molecule. The voids also become more elongated. The broad orientational distribution of voids observed in pure DPPC is, with a 30% molar concentration of cholesterol, replaced by a distribution where orientation along the bilayer normal is favored. Our results suggest that instead of being uniformly distributed to the whole bilayer, these effects are localized to the close vicinity of cholesterol molecules.

The role of cholesterol in membrane fusion

“…Generally, we can distinguish between (i) global effects of the perturbed lipid bilayer, discussed in the previous section, on membrane protein behavior and (ii) specific effects of cholesterol binding to defined binding motifs on membrane proteins. The increased order of the lipid acyl chains results in a reduction of free volume in bilayers when cholesterol is introduced (Falck et al, 2004). This increased free volume changes the conformational behavior and shifts conformational equilibria of membrane proteins in the presence of cholesterol.…”

On Physical Properties of Tetraether Lipid Membranes: Effects of Cyclopentane Rings

“…Relative volume fluctuations of PLFE liposomes at any given temperature examined were 1.6–2.2 times more damped than those found in DPPC liposomes [50]. Volume fluctuations are closely related to solute permeation across lipid membranes [51] and lateral motion of membrane components [52]. Thus, the low values of relative volume fluctuations explain why PLFE liposomes exhibit unusually low proton permeation and dye leakage [45, 46] as well as limited lateral mobility, especially at low temperatures (e.g., <26°C) [43, 53].…”

Significance of Sterol Structural Specificity

“…A semi-isotropic scheme for pressure control was employed, and the particle mesh Ewald method (38) was used for electrostatics. A more detailed description of the simulation protocol used in this study can be found elsewhere (39,40).…”